A major challenge in allogeneic hematopoietic cell transplantation is how to transfer the beneficial effects mediated by T cells without causing graft-versus-host disease (GVHD). Our long-term goal is to develop a clinically relevant strategy that allows transfer of allogeneic T-cell immunity against malignancies and infectious pathogens without causing GVHD. The objective of this application, which is the next step toward achieving this goal, is to further characterize and develop our central hypothesis that memory T cells do not cause severe GVHD. We also hypothesize that memory T cells have the potential to provide robust anti-infective and anti-malignancy activity. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1)To delineate the mechanism by which memory T cells have decreased ability to induce GVHD; 2)To determine the anti-tumor potential of memory T cells; and 3)To conduct a Phase I clinical trial using memory T cells to promote immune recovery without GVHD induction. Under the first aim, the mechanism by which memory T cells have decreased ability to induce GVHD will be studied using both a classic and a novel GVHD model mediated by allospecific transgenic T cells. Under the second aim, we will analyze the anti-tumor activity of memory T cells and test whether the anti-tumor activity can be enhanced by vaccination of the donor. Under the last aim, we will determine the safety of a naive T-cell depleted donor lymphocyte infusion given to recipients of haploidentical allogeneic hematopoietic cell transplantation. The impact on post-transplant immune recovery will also be studied. The proposed research is an important step toward use of this innovative approach for prevention of GVHD in humans. The proposed research is significant, because this approach has great potential to improve the safety and to broaden the scope and effectiveness of allogeneic hematopoietic cell transplantation. It is also expected that the results will fundamentally advance the understanding of how memory T cells respond to alloantigens.